Natural killer-like T (NKT) cells are a distinct population of T lymphocytes with enormous therapeutic potential in the treatment of diseases such as cancer and autoimmune disorders. Invariant natural killer T (iNKT) cells form a subset of regulatory T cells with features of both innate and adaptive immunity. In contrast to conventional T cells that are activated by a peptide presented by an MHC class I or II molecule, iNKT cells recognize lipid derivatives present in the context of CD1d, a non-classical MHC I molecule expressed on antigen presenting cells (APCs).
α-GalCer (α-galactosylceramide), a glycolipid composed of α-linked galactose, sphingosine, and an acyl tail, was obtained by structural optimization of agelasphin, which is isolated from the marine sponge Agelas mauritianus. It has been found to exhibit antitumor activity both in vitro and in vivo and shown to be the most potent ligand yet known for both mouse and human invariant natural killer T cells (iNKT cells).
Invariant NKT cells (iNKT cells) carry the invariant TCR-α chain (Vα14/Jα18 in mice and Vα24/Jα18 in humans) and co-express CD161 antigen (NK cell marker NK1.1 in mice and NKR-P1A in humans). (1) Lantz, O.; Bendelac, A. J. Exp. Med. 1994, 180, 1097; (2) Dellabona, P.; Padovan, E.; Casorati, G.; Brockhaus, M.; Lanzavecchia, A. J. Exp. Med. 1994, 180, 1171; (3) Makino, Y.; Kanno, R.; Ito, T.; Higashino, K.; Taniguchi, M. Int. Immunol. 1995, 7, 1157; and (4) Davodeau, F.; Peyrat, M. A.; Necker, A.; Dominici, R.; Blanchard, F.; Leget, C.; Gaschet, J.; Costa, P.; Jacques, Y.; Godard, A.; Vie, H.; Poggi, A.; Romagne, F.; Bonneville, M. J. Immunol. 1997, 158, 5603. They secrete large amounts of Th1 (e.g., IFN-γ, IL-2) and Th2 (e.g., IL-4, IL-6) cytokines in response to αGalCer presented by the CD1d molecule on the antigen-presenting cells.5-9 (5) Kawano, T.; Cui, J.; Koezuka, Y.; Toura, I.; Kaneko, Y.; Motoki, K.; Ueno, H.; Nakagawa, R.; Sato, H.; Kondo, E.; Koseki, H.; Taniguchi, M. Science 1997, 278, 1626; (6) Yoshimoto, T.; Paul, W. E. J. Exp. Med. 1994, 179, 1285; (7) Arase, H.; Arase, N.; Nakagawa, K.; Good, R. A.; Onoe, K. Eur. J. Immunol. 1993, 23, 307; (8) Kawakami, K.; Yamamoto, N.; Kinjo, Y.; Miyagi, K.; Nakasone, C.; Uezu, K.; Kinjo, T.; Nakayama, T.; Taniguchi, M.; Saito, A. Eur. J. Immunol. 2003, 33, 3322; and (9) Nieuwenhuis, E. E.; Matsumoto, T.; Exley, M.; Schleipman, R. A.; Glickman, J; Bailey, D. T.; Corazza, N.; Colgan, S. P.; Onderdonk, A. B.; Blumberg, R. S. Nat. Med. 2002, 8, 588. These secreted cytokines could then transactivate downstream immune cells, including dendritic cells (DC), natural killer cells (NK), B cells, CD4+ T and CD8+ T cells, and thereby bridging the innate and adaptive immunity.10-12 (10) Eberl, G.; MacDonald, H. R. Eur. J. Immunol. 2000, 30, 985; (11) Eberl, G.; Brawand, P.; MacDonald, H. R. J. Immunol. 2000, 165, 4305; and (12) Kitamura, H.; Ohta, A.; Sekimoto, M.; Sato, M.; Iwakabe, K.; Nakui, M.; Yahata, T.; Meng, H.; Koda, T.; Nishimura, S.; Kawano, T.; Taniguchi, M.; Nishimura, T. Cell. Immunol. 2000, 199, 37.
However, the counterbalance of Th1 and Th2 cytokines may limit the clinical application of αGalCer for the treatment of a variety of disorders.13-16 (13) Tahir, S. M.; Cheng, O.; Shaulov, A.; Koezuka, Y.; Bubley, G. J.; Wilson, S. B.; Balk, S. P.; Exley, M. A. J. Immunol. 2001, 167, 4046; (14) Dhodapkar, M. V.; Geller, M. D.; Chang, D. H.; Shimizu, K.; Fujii, S.; Dhodapkar, K. M.; Krasovsky, J. J. Exp. Med. 2003, 197, 1667; (15) Giaccone, G.; Punt, C. J.; Ando, Y.; Ruijter, R.; Nishi, N.; Peters, M.; von Blomberg, B. M.; Scheper, R. J.; van der Vliet, H. J.; van den Eertwegh, A. J.; Roelvink, M.; Beijnen, J.; Zwierzina, H.; Pinedo, H. M. Clin. Cancer Res. 2002, 8, 3702; and (16) Bricard, G.; Cesson, V.; Devevre, E.; Bouzourene, H.; Barbey, C.; Rufer, N.; Im, J. S.; Alves, P. M.; Martinet, O.; Halide, N.; Cerottini, J. C.; Romero, P.; Porcelli, S. A.; Macdonald, H. R.; Speiser, D. E. J. Immunol. 2009, 182, 5140.